The lipoxygenases are a family of enzymes which catalyze the oxygenation of arachidonic acid. The enzyme 5-lipoxygenase converts arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This is the first step in the metabolic pathway yielding S-hydroxyeicosatetraenoic acid (5-HETE) and the important class of mediators, the leukotrienes (LTs).
Similarly, 12-and 15-lipoxygenase, convert arachidonic acid to 12-and 15-HPETE, respectively. Biochemical reduction of 12-HPETE leads to 12-HETE, while 15-HPETE is the precursor of the class of biological agents known as the lipoxins.
A variety of biological effects are associated with these products from lipoxygenase metabolism of arachidonic acid and they have been implicated as mediators in various disease states. For example, the leukotrienes LTC.sub.4 and LTD.sub.4 are potent constrictors of human airways in vitro, and aerosol administration of these substances to non-asthmatic volunteers induces broncho-constriction. LTB.sub.4 and 5-HETE are potent chemotactic factors for inflammatory cells such as polymorphonuclear leukocytes. They also have been found in the synovial fluid of rheumatoid arthritic patients. Leukotrienes have also been implicated as important mediators in asthma, rheumatoid arthritis, gout, psoriasis, allergic rhinitis, adult respiratory distress syndrome, Crohn's disease, endotoxin shock, inflammatory bowel disease and/or ischemia-induced myocardial or brain injury, among others. The biological activity of the leukotrienes has been reviewed by Lewis and Austen (J. Clinical Invest, 73: 889 (1984)) and by J. Sirois (Adv. Lipid Res. 21: 78 (1985)).
The product 12-HETE has been found in high levels in epidermal tissue of patients with psoriasis. The lipoxins have recently been shown to stimulate elastase and superoxide ion release from neutrophils. Thus, lipoxygenase enzymes are believed to play an important role in the biosynthesis of mediators of asthma, allergy, arthritis, psoriasis, and inflammation. It is postulated that interrupting the biochemical pathways involved in the vanous manifestations of these disease states will provide effective systemic and/or symptomatic treatment of these diseases.
It is therefore an object of this invention to provide compounds which inhibit lipoxygenase enzymes. A further object is the identification of prodrug derivatives of lipoxygenase inhibitors having an added, metabolically cleavable group. By the removal of their cleavable groups, these prodrugs are converted in vivo to active lipoxygenase inhibitors. Such prodrugs have been shown to be useful, for example, in improving the bioavailability of pharmaceuticals by enhancing their solubility, stability, and/or rate of absorption.